Pyrimidine compounds and processes



Patented Mar. 16, 1948 PYRIMIDINE COMPOUNDS AND PROCESSES FOR MAKING THE SAME Francis Henry Swinden Curd, Clifford Gordon Raison,

and Francis Leslie Rose, Blackley,

Manchester, England, assignors to Imperial Chemical Industries Limited, a corporationof Great Britain No Drawing. Application May 26, 1944, Serial No. 537,536. In Great Britain June 11, L943 13 Claims. i

This invention relates to new pyrimidine compounds and to processes for manufacturing the same. The said new compounds, which will be more closely defined hereinafter, may be described broadly as pyrimidines bearing in the 2- position an arylamino group, and in the 4-position a strongly basic substituent derived from a diamine which is at least in part aliphatic or alicyclic, and optionally bearing other substituents in the 5- and S-positions. They are useful as chemotherapeutic agents and have properties such as make them particularly valuable as antimalarial agents.

It is an object of this invention to provide new pyrimidine compounds. A further object is to provide new chemotherapeutic agents. A further object is to provide new and valuable antimalarial agents. Another object is to provide processes for manufacturing new pyrimidine compounds. A further object is to provide processes for making new anti-malarial agents. Futher objects will appear hereinafter as the description proceeds. These and other objects are achieved by the following invention.

The said new compounds are pyrimidine derivatives which may be represented by the formula Am-C f'| Y 1 I( 3-NH-ANRR' wherein Am represents an arylamino group which may be unsubstituted or may bear one or more simple non-acidic substituents such, for example, as halogen atoms, nitro groups, hydrocarbon radicals (which themselves may optionally bear simple substituents and which may be attached to the arylamino group directly or through an oxygen or sulphur atom or through an imino, sulphonyl, or carbonyl group), alkoxy groups, alkylmercapto groups, cyano groups or esterified carboxyl groups; A is a linking group which is aliphatic or alicyclic or aliphatic-carbocyclic and may be substituted, for example, by hydrocarbon radicals, hydroxy or alkoxy groups or dialkylaminoalkyl groups, and where A or part of A is an aliphatic chain it may be interrupted by oxygen or sulphur atoms or imino groups; NRR' is a strongly basic amino or substituted amino group such as alkylamino or dialkylamino or piperidino or other strongly basic nitrogen-containing heterocyclic group; X is hydrogen or a hydrocarbon radical and Y is hydrogen or a simple neutral substituent such for example as a hydrocarbon radical, a halogen atom, an alkoxy or aryloxy or arylmercapto group or a cyano the symbols A, R, R, X and Y havin the same meanings as before and Z representing a labile group such as a halogen. atom .or a hydro-.- carbon radical which is attached by means of an ether or thioether linkage, tor example,,a n alhoxy, aryloxy or alkylmercapto group.

The reaction is conveniently brought about by heating the reagents together, optionally in presence .of a solvent or diluent. If desired, the arylamino-pyrimidine compound or the diamine may be used in the form of .a salt, such as the hydrochloride or acetate. Also, if desired the reaction may be carried out in presence of an acid-binding agent such as sodium hydroxide.

The reagents are conveniently, but not necessarily, used in approximately stoichiometric proportions. Actually we prefer to use about 1.215 molecular proportions of the diamine, but {the proportions are not critical and if desired a large excess of the diamine may be used so that it fzunctions as a solvent or diluent.

The i-halogeno-pyrimidine compounds-used as starting materials may be made by reaction of a halogenating agent such as phosphorus oxychloride or .oxybromide with the products of inter.- action of appropriate ary-lamines and 2-,alkylmercapto -4.- hydroxy =p yrimidines (the latter compounds being themselves conveniently obtai-ned by interaction of alkyl isothioureas with appropriately substituted iormylacetic -ester, S-)--v see, for example, our copending applications Serial Nos. 552,382 and 552,383, now Patents os. 2,433,489 and 2,433,440, respectively, issued De-i cember 30, 1947. The alternative starting materials containing ether or thioether groups can readily be made by interaction of the 4-hal0g8no derivatives with the appropriate hydroxy or merecapto compounds or with alkali metal derivatives .of such compounds.

As examples of suitable 4-substituted-2earylamino-pyrimidine intermediates there may be mentioned,

4-chloro-2-ani1ino-6-methylpyrimidine, 4-chloro-2- (4'-chloroanilino) -pyrimidine,

3 4 chloro 2 (4' chloroanilino) 6 methyl pyrimidine, 4-chloro-2-(4'-methylanilino) -pyrimidine 4 chloro 2 (4 methylanilino) 6 methyl pyrimidine,

4 chloro 2 -(4' methoxyanilino) 6 meth ylpyrimidine,

4 chloro 2 (4' methylmercaptoanilino) 6 methylpyrimidine,

4 chloro 2 (3' chloroanilino) 6 methyl pyrimidine,

4 chloro 2 (2' chloroanilino) 6 methyl pyrimidine,

4 chloro 2 (3 methylanilino) 6 methyl pyrimidine,

4 chloro 2 (2' methylanilino) 6 methyl pyrimidine,

4 chloro 2 (2'24' dichloroanilino) 6 methylpyrimidine,

4 chloro 2 (3':4' dichloroanilino) 6 methylpyrimidine,

4 chloro 2 (2:5 dichloroanilino) 6 methylpyrimidine,

4 chloro 2 (2 methyl 4' chloroanilino) fi-methylpyrimidine,

4 chloro 2 (3' chloro 4' methylanilino) B-methylpyrimidine,

4 chloro 2 (3':4' dimethylanilino) 6 methylpyrimidine,-

4 chloro 2 (3:5' dimethylanilino) 6 methylpyrimidine,

4 chloro 2 (2' methoxyanilino) 6 meth ylpyrimidine,

4 chloro 2 (3z5' dibromoanilino) 6 methylpyrimidine,

4 chloro- 2- (4' dimethylamino anilino) 6 methylpyrimidine,

4 chloro 2 (4' chloroanilino) -5 bromo 6 methylpyrimidine,

4 chloro 2 (4 chloroanilino) 6 phenyl pyrimidine,

4 chloro 2 (4' chloroanilino) 5 phenyl pyrimidine,

4 chloro 2 (4 methoxyanilino) 5 phen ylpyrimidine,

4 chloro 2 (4' chloroanilino) 5 methyl pyrimidine,

4 chloro 2 (4' chloroanilino) 5:6 di

methylpyrimidine,

4 chloro 2 (4' -chloroanilino) 5 ethyl 6 methylpyrimidine,

4 chloro 2 (2' naphthylamino) 6 meth ylpyrimidine,

4 chloro 2 (6 bromo 2"- naphthyl amino) -6-methylpyrimidine,

4 chloro 2 (6 methoxy 2' naphthyl amino) -6-methylpyrimidine,

4 chloro 2 (1' naphthylamino) 6 meth ylpyrimidine,

4 chloro 2 (4 chloro 1' naphthyl amino)-6-methylpyrlmidine,

'4 chloro 2 (4' ethoxyanilino) 6 methyl methylpyrimidine,

4 chloro 2 (4' phenylanilino) 6 methyl pyrimidine,

4 chloro 2 (4' nitroanilino) 6 methyl pyrimidine,

4 chloro 2 (4' cyanoanilino) 6 methyl pyrimidine,

4 4 chloro 2 (4' chloroanilino) 5 phenoxy pyrimidine and 4 chloro 2 (4 chloroanilino) 5 benzyl 6-methylpyrimidine.

Also the corresponding 4-bromo-, 4-phenoxy-, 4-ethoxy-, 4-methylmercapto-, 4-ethylmercaptoand 4-phenylmercaptocompounds may be used.

As examples of suitable diamines there may be mentioned ethylenediamine, 2 dimethylamino ethylamine, 2-diethylaminoethylamine, 3-dimethylaminopropylamine, 3 diethylaminopropyl amine, 4 diethylaminobutylamine, 4 diethylamino 1 methylbutylamine, 3 diethylamino 1:2 dimethylpropylamine 3 diethylamino 2 hydroxypropylamine, 2 methylaminoethyl amine, 3 butylaminopropylamine, 3 diethyl aminoethoxypropylamine, 3 diethylaminoethyl mercaptopropylamine, 5 diethylamino l aminopentane, 2 pyrollidinoethylamine, 1:3 bis diethylamino propylamine 2, N ethyl N: ,8 diethylaminoethyl ethylenediamine, 2 piperidinoethylamine, 3 piperidinopropylamine, p dimethylaminoethoxy aniline, p diethyl aminoethoxy aniline, p diethylaminoethyl mercapto aniline, 3 diethylamino 2:2 di methylproplyamine and 3-di-n-butylaminopropylamine.

A further feature of our invention is a modified process wherein the basic 4-substituent is introduced by stages. Thus the arylaminopyrimidine compound carrying a labile group in the 4-position is brought into reaction with an amino-compound of the form NH2-AB where A represents either the whole or part of the linking group A defined above and where B stands for a reactive group which is then converted by known methods into the amino group NRR' or into a group A"NRR' such that A and A together constitute the linking group A. For example the group B may be a hydroxy group or a derivative thereof which is, or is readily convertible to, a reactive ester thereof, such as a halide, this then being brought into reaction with an amine NHRR' or an amino substituted amine or a hydroxyor mercapto-substituted amine HO-A"NRR' or HSA--NRR' (or an alkali metal derivative of such a compound) such that A'NH A", A'OA' or AS--A"' constitutes the linking group A previously mentioned, Another alternative is to bring the labile group Z into reaction with a diamine whereof one amino group is protected, as by acylation, and then to remove any such protecting group. Further, if desired, the free amino group so generated may be modified, as by alkylation, conversion to a heterocyclic group such as piperdino or by bringing it into reaction with a halogeno-substituted amine Hal-A"NRR' such that A'NH constitutes the linking group A.

These 2-arylaminopyrimidines carrying a basic substituent in the 4-position and optionally bearing other substituents in the 5- and 6-positions are new compounds. They are strongly basic colourless or pale yellow viscous oils or colourless crystalline solids. Where the bases are oils the p-icrates which are crystalline, may be used for purposes of characterisation. The bases form colourless salts with mineral and organic acids. The salts with mineral acids such as hydrogen halides, sulphuric and phosphoric acids or with lower organic acids such as acetic, lactic, tartaric and lower alkanesulphonic acids (e. g. methanesulphonic acid) are water-soluble. The salts with acids of highe molecular weight such as methylene bis-2:3-hydroxynaphthoic acid and methylene bis-salicylic acid are more sparingly soluble in water.

The following examples illustrate, but do not limit, the invention. The parts are by weight.

Example 1 25.4 parts of 4-chloro-2-p-chloroanilino6- methylpyrimidine and. 1 .25 parts of diethyl aminoethyl amine are stirred and heated together at 120-13D C. fo 6 hours. The resulting melt is dissolved in 500 parts of hot dilute hydrochloric acid. After cooling, the solution is basified with caustic soda solution and the base which is liberated as an oil is extracted with chloroform. The chloroform extract is shaken twice with 250 parts of 5% aqueous acetic acid. The aqueous extracts are combined, and basin-ed with caustic soda solution. The liberated base is extracted with chloroform and the chloroform extract is ried over potassium carbonate and evaporated. The residual oil is then distilled in vacuo. 4- 3- diethylaminoethylamino 2 p chloroanilino-(imethyl-pyrimidine distils over at 224226 (LE/0.03 mm. It forms a dipicrate which crystallises from c-ethoxy-ethanol in thick yellow prisms, l-ll. P. 219-22- C.

The base can be converted into its dihydrochloride by dissolving it in an excess of Z-normal hydrochloric acid and evaporating the resulting solution in vacuo at 50-55 C. The residue is dried and crystallised from a miXture of ethyl alcohol and ethyl acetate and finally from ethyl alcohol. 4-,8-diethylaminoethylamino-Z-p-chloro-anilinmfi-Inethylpyrimidine dihydrochloride is thus obtained, M. P. 270-271 C. (decomp).

In a similar manner from 1-chloro-2-p-chloroaniline-6-methylpyrimidine and l-diethylamino- 2-anlino-propane there is obtained l-y-diethylaminopropylamino-Z- p chloroanilino-S-methylpyrimidine (B. P. 225 C./O. l mm.). The picrate has melting point 219 C. after recrystallisation from B-ethoxyethanol. The corresponding dihydrochloride melts at 252 25 C. after crystallisation from ethanol. t is readily soluble in water.

Likewise from -chloro-2-p-chloroanilino-6- methylpyrimidine and l-diethylamino-a-aminopentane, 4--5diethylamino-a-rnethylbutylamino- 2-p-chloroanilino-6-methylpyrimidine is obtained as a clear yellow viscous oil B. P. 210 C./0.9 mm. The picrate crystallises from a mixture of B-ethoxyethanol and ethanol in yellow needles. M. P. 168-170 C. The dihydrochloride melts at 234-237 C. after crystallisation from a mixture of ethanol and ethyl acetate, from which it separates in colourless needles.

In a corresponding manner from 4-chloro-2-pchloroalinino-6-methylpyrimidine and l diethylaniino l-aminobutane, e- 5 -diethylarninobutylamino-2-p-chloroanilino-S-methylpyrimidine is obtained. The dihydrochloride melts at 2l5-2l7 C. after crystallisation from ethanol. It forms colourless needles.

Likewise from l-chloro-Z-p-chloroanilino-6- methylpyrimidine and l-dirnethylamino-S-aminopropane there is obtained l-y-dimethylaminm propylamino-Z-p-chloroanilino- G-methylpyrimidine. the dihydrochloride of which, crystallised from a mixture of ethanol and ethyl acetate, has M. P. 231-234 C.

Similarly by interaction of 4=chloro-2-p-chlo- 6. roanilino-G-methylpyrimidine with l-piperldino- 3-aminopropane there is obtained 4-v-piperidinopropyl-amino-2-p-chloroanilino-B-methylpyrlmidine, the dihydrochloride of which melts at 289- 292 C.

By interaction of 4-chloroe2-p -chloroanilino- 6 methylpyrimidine and p- (,8 diethylaminoethoxy)-aniline there is formed l-p-(B-diethylaminoethoxy) anilino 2 p chloroanilino 6 methylpyrimidine which after crystallisation from ethanol has M. P. -152 C.

Again by interaction of 4-chloro-2-p-chloroaniline-6-methylpyrimidine with l-n-butylamino-3-aminopropane there is obtained 4-Y-n-butylamino-propylamino 2 p-chloroanilino 6- methylpyrimidine, the dihydrochloride of which melts with decomposition at 232-235 C.

Example 2 12.7 parts of 4-chloro-2-p-chloro-anilino-6- methylpyrimidine, 5.1 parts of Z-dimethylaminoethylamine and 3.75 parts of glacial acetic acid are stirred and heated together for 3 hours at C. The resulting reaction mixture is dissolved in 250 parts of hot dilute hydrochloric acid. After filtering from a little undissolved matter the solution is basified with caustic soda solution and the precipitated oil is extracted with chloroform. The chloroform extract is shaken twice with 1G0 parts of 5% acetic acid, the aqueous extracts combined and basified with caustic soda solution. The base is separated oil and dissolved in hot 2-normal hydrochloric acid. On cooling, the dihydrochloride of -p-dimethylaminoethylamino-2-p-chloroanilino 6 methylpyrimidine crystallises out. It is filtered off and washed with acetone. By recrystallisation from ethanol it is obtained as colourless needles, melting point 213-215 C.

Example 3 15.5 parts of 2-p--chloroanilinol-phenoxy-G- methylpyrimidine (M. P. 126-127 C. made by heating 4-chloro-2-p-chloroanilino-6-methylpyrimidine with sodium phenate in phenol) and 7.25 parts of B-diethylaminoethylamine are heated together in 45 parts of phenol for 8 hours at 120-130 C. with stirring. After cooling somewhat, the still molten reaction mixture is poured into an excess of dilute caustic soda and the oil which separates out is extracted with chloroform. The chloroform extract is shaken twice with 100 parts of 5% aqueous acetic acid and the aqueous extracts are combined and basified with caustic soda solution. The oil is separated oil and dissolved in 100 parts of 7% hydrochloric acid. This solution is evaporated to dryness under diminished pressure at 50-60 C. and the residue is crystallised from ethanol whereby 2-p-chloroanilino-4 B diethylaminoethylamino-fi-methylpyrimidine dihydrochloride is obtained; it has M. P. 269 270 C.

Working in the same way with 10.4 parts of the dihydrochloride, or 8.5 parts of the monohydrochloride, of ,B-diethylaminoethylamine instead of the 7.25 parts of the free base used in the process just described, better yields of 2-p-chloroanilino--pdiethylaminoethylamino -6- methylpyrimidine dihydrochloride are obtained.

By working in the way described above, but using instead of the 7.25 parts of p-diethylarninoethylamine, 8.1 parts of y-diethylaminopropylamine, there is obtained 2-p-chloroanilino-4-ydiethylaminopropylamino 6 methylpyrimidine dihydrochloride of M. P. 249-250 C.

Again by using 11.3 parts of the dihydrochloride or 9.3 parts of the monohydrochloride instead of the 8.1 parts of the free y-diethylaminopropylamine and working in the manner just described improved yields of 2-p-chloroanilino-4- 'y diethylaminopropylamino-G-methylpyrimidine dihydrochloride are obtained.

Example 4 25.4 parts of 4-ch1oro-Z-p-chloroanilino-G- methylpyrimidine and 12.2 parts of ethanolamine are stirred and heated together at 120 -130 C. for 10 hours. The resulting melt is heated with 300 parts of water and the solid thereby obtained is filtered off. It is then stirred with dilute caustic soda solution, again filtered and washed well with water. By crystallisation from methanol 2-p chloroanilino 4 3 hydroxyethylamino-6 methylpyrimidine is obtained, M. P. 157-158 C. It forms a hydrochloride, M. P. 2l8-219 C. which is sparingly soluble in water.

14 parts of 2-p-chloroanilino-4-p-hydroxyethylamino-S-methylpyrimidine and 42 parts of phosphorus oxychloride are refluxed together for 15 minutes. The excess of phosphorus oxychloride is then removed by distillation in vacuo at 50-60 C. The residue is added to crushed ice and the mixture is stirred and then allowed to stand for 2 hours. The product which separates is then filtered off and dissolved in ethanol. Concentrated hydrochloric acid is added to the solution whereupon 2-p-chloroanilino-4-fi-chloroethylamino-6- methylpyrimidine hydrochloride separates in flat needles, M. P. 290-291 C.

11.1 parts of 2-p-chloroanilino-4-B-chloroethylamino-6-methylpyrimidine hydrochloride and 30 parts of diethylamine are heated in a closed vessel at 140 C. for 8 hours. The vessel is then opened and any excess of dimethylamine is distilled off by heating the contents to 100 C. for 2 hours at atmospheric pressure. The residue is dissolved in 250 parts of hot dilute hydrochloric acid. After cooling, the solution is basified with caustic soda solution and the oily base which is liberated is extracted with chloroform. The chloroform solution is shaken twice with 150 parts of acetic acid solution. The aqueous extracts are combined and basified with caustic soda solution. The liberated base is extracted with chloroform and the chloroform extract is dried over anhydrous potassium carbonate. The chloroform is distilled off and the residual oil is distilled in vacuo. The fraction of B. P. 215-225 C./0.01- 0.15 mm. is collected and consists of 4-p-diethylaminoethylamino-Z- p-chloroanilino 6 methylpyrimidine, The picrate of the base melts at 2l'7-219 C. after crystallisation from B-ethoxyethanol.

Example 5 11.5 parts of 4-chloro-2-(4'-dimethy1-aminoanilino)-6-methylpyrimidine and 7.1 parts of -diethylaminopropylamine are heated together for 8 hours at 120-130 C. After cooling, the reaction mixture is dissolved in dilute hydrochloric acid and the solution is basified with caustic soda solution. The base, which is liberated as an oil, is extracted with chloroform. The chloroform solution is extracted twice with 300 parts of 5% acetic acid and the acid extracts are combined and basified with caustic soda solution. The base is extracted with chloroform, the solution is dried, and the chloroform is distilled oil in vacuo. The residue, which is 4-' -diethylaminopropylamino-2- (4'-dimethylaminoanilino) G-methylpyrimidine, is dissolved in hydrobromic acid and acetic is added, whereupon the trihydrobromide is precipitated. It is filtered off, washed with acetone, dried and crystallised from ethanol. It has M. P. 256-258 C,

Earample 6 32.3 parts of 4-chloro-2-p-naphthylamino-6- methylpyrimidine and 17.4 parts of diethylamlnoethylamine are stirred and heated together at -130 C. for 10 hours. The resulting melt is dissolved in 600 parts of dilute hydrochloric acid. After basification with caustic soda the base, which is liberated as an oil, is extracted with ether. The ether extract is shaken twice with 250 parts of 5% aqueous acetic acid, the aqueous extracts are combined and basified with caustic soda solution. The base which is liberated is separated off and stirred with 300 parts of 2-Normal hydrochloric acid. The hydrochloride which separates out is filtered off, washed with acetone and dried at 60-65" C. It is purified by crystallisation from ethanol. l-e-diethylaminoethylamino 2 c-naphthylamino-6-methylpyrimidine dihydrochloride is thus obtained as colourless needles, M. P 252-254 C. (decomp.).

In a corresponding manner from 4-chloro-2-flnaphthylamino-G-methylpyrimidine and l-diethylamino 3 aminopropane the 4-'y-diethylaminopropylamino 2 p naphthylamino 6 methylpyrimidine is obtained. The dihydrochloride melts at 259-260 (decomp.) after crystallisation from a mixture of ethanol and ethyl acetate and is readily soluble in water.

Similarly from 4-chloro-Z-c-naphthylamino- 6 methylpyrimidine and 1 diethylamino 4 aminopentane the 4-t-diethylamino-u-methylbutylamino 2-p-naphthylamino-G-methylpyrimidine is obtained. The dihydrochloride melts at 268-270 C. (with decomp.), after crystallisation from a mixture of ethanol and ethyl acetate.

Likewise from 4-chloro-2-e-naphthylamino-6- methylpyrimidine and l-diethylamino-a-aminobutane the 4 a diethylaminobutylamino-2-pnaphthylamino-G-methylpyrimidine is obtained. The dihydrochloride melts at 262263 C. (decomp.) after crystallisation from a mixture of ethanol and ethyl acetate.

Again from a-chloro 2 p naphthylamino-G- methylpyrimidine and p- (fi-diethylaminoethoxy) aniline, 4-p-(p-diethylaminoethoxy) anilino-2- ,3 naphthylamino 6 methylpyrimidine is obtained. The dihydrochloride crystallised from ethanol, melts at 269-271 C. (decomp.).

Example 7 .7 parts of 4 chloro 2 (6' methoxy-2'- naphthylamino) 6 methylpyrimidine and 5.7 parts of p-diethylaminoethylamine are stirred and heated at 120-130 C. for 6 /2 hours. The resulting melt is dissolved in dilute hydrochloric acid and the solution is basified with caustic soda solution. The oily base which is liberated is extracted with ether. The ether extract is shaken with 250 parts of 5% aqueous acetic acid and the aqueous extract is again basified with caustic soda solution. The liberated oil is separated ofi and dissolved in 60 parts of 2 N hydrochloric acid. The solution is evaporated to dryness in vacuo at 50-60 C. and the solid residue is stirred with acetone and filtered. The solid is washed with acetone and dried at 60-65 C. It is purified by crystallisation from aqueous ethanol. 4-p-diethylaminoethylamino 2 -(6-methoxy-2'-naphthylamino)-6-methylpyrimidine dihydrochloride G-methyIpyrimidine, the

chloride of which meltsat 259-260" C. (decomp.)..

From 4 chloro 2 (6 bromo-Zmaphthylamino) 6 methylpyrimi'dine and 1/dimti'1} 1- 'aminopropylamine there is obtained 4i -'dimethylaminopropylamino-2- (6' -bromo-2' -naphthylamino) 6 methylpyrimidine, the dihydrochloride of which melts at 234F236 C. (decomp.).

From -chloro -2-(6- bromo -2- naphthylamino) -6 methylpyrimidine and c-dimethylaminoethylarnine there is obtained d-B-dimethylaminoethylamino -2-(6- bromo -2'- naphthyL- amino) -'6- methylpyrimidine, thedihydrochlorideof which melts at 276-278 C. (decoiriql).

From 4-chloro -2-(6'- 'bromo -2- naphthylamino) -6methylpyrirnidine and Y-piperidinopropylamine there is obtained d-y-piperidinopropylamino-2-(6 bromo -2'- naphthylamino)- dihydrochloride of which melts at 256258 C.

Example 8 9.75 parts of 4-chloro-2-(3-chloroanilino)-6- methylpyrimidine and 6.25 parts of w-diethylaminopropylamine are heated together at 120- 130 C. with stirring for 8 hours. The reaction mixture is then dissolved in 200 parts of dilute hydrochloric acid, cooled and basified with caustic soda solution. The oily base which is precipitated is extracted with chloroform and this chloroform solution extracted twice with 100 parts of aqueous acetic acid. The acetic acid extracts are combined and basified with caustic soda solution. The liberated base is again extracted with chloroform and the chloroform solution extracted with 2-normal hydrochloric acid chloroanilino) -6- methylpyrimidine and ,B-diethylamino-ethylamine, 4,8-diethylaminoethylamino-Z- (2-chloroanilino) -6- methylpyrimidine is obtained. its dihydrochloride has M. P. 25l253 C.

Example 9 parts of 4-chloro-2-(2':4'-dichloroanilino)- fi rn'ethylpyrimidine and 10.8 parts of 'y-diethylaminoprcpylamine are intimately mixed and heated together for 8 hours at l20130 C. After cooling, the reaction mixture isdissolved in dilute hydrochloric acid. It is then basified with caustic soda solution andthe liberated base is extracted with chloroform. The chloroform solution is extracted twice with 250 parts of 5% aqueous acetic acid and the acid extracts are combined and basified with caustic soda solution. The base thus liberated, which is -v-diethylaminopropylamino 2 (2'24' dichloroanilino) -6- methylpyrimidine, is separated ofi and purified by distillation under high vacuum. It has B. P. 208- 210 C./0.02 mm. and forms a picrate which,.after crystallisation from ,B-ethoxyethanol, melts at To form the -dihydrochloride the base is dissolved in 2-normal hydrochloric acid and concentrated hydrochloric acid is added whereupon the hydrochloride slowly crystallises out. It may be further purified by dissolving it in water and reprecipitating by addition of concentrated hydrochloric acid. It then melts at 208-210 'C.

In a similar manner, from 4-chloro-2-(3":4'- dichloroanilino)-6-methylpyrimidine and 'y-diethylaminopropylamine there is obtained 4-ry-diethylaminopropylamino 2 (3':4' dichloroaniline) -6-methylpyrimidine. Its dihydrochloride has M. P. 237-239C.

Also from l-chloro-Z-(Z':5'-dichloroanilino)- 6-methylpyrimidine and v-diethylamino-propylamine there is obtained 4-v-diethylaminopropylamino-2-(2':5'-dichloroanilino) 6 methylpyrirnidine of M. P. 98-l00 C. (decomp.). The dihydrochloride melts at 248-250 C.

Example 10 25 parts of 4-chloro-2-(4-methoxyanilino) -6- methylpyrimidine and 14 parts of B-diethylaminoethylamine are mixed and heated together at 126-130 C. for 6 hours. After cooling the reaction mixture is dissolved in dilute hydrochloric acid. It is then basified with caustic soda solution and the liberated base is extracted with ether. The ether solution is extracted twice with 200 parts of 5% acetic acid, the acid extracts combined and basified with caustic soda solution. The base is separated ofi and dissolved in parts of 2-normal hydrochloric acid and the solution evaporated to dryness in vacuo at 50-60 C. The dihydrochlorideof 4-d-diethylamino-ethylamino- 2-( l-methoxyanilino) 6 methylpyrimidine which remains is purified by crystallisation from ethyl alcohol and then has M. P. 23l-232 C.

In a similar way from 4-chloro-2-(2'-methoxyaniline) 6 methylpyrimidine and e-diethylaminoethylamine there is obtained l-fi-diethylaminoethylamino 2-(2' methoXyanilino)-6- ,methylpyrimidine, the dihydrochloride of which has 'M. P. 272-273 C.

From 4-chloro-2-(2'-methylanilino) -6-methylpyrimidine and the same diamine there is obtained 4 p diethylaminoethylamino-2-(2- methylanilino) 6 methylpyrimidine, the dihydrochloride of which has M. P. 237-238 C.

From 4-chloro-2- (3'-methy1anilino) -6-methy1- pyrimidine and S-diethylaminoethylamine there is obtained 4 5-diethylaminoethylamino-2-(3'- methylanilino) 6 methylpyrimidine, the dihydrochloride of which has M. P. 2'72-274 C.

From 4-chloro-2- (4'-ethoxyanilino) -6-methylpyrimidine and fi-diethylaminoethylamine there is obtained 4-fi-diethylaminoethylamino-2-(4'- ethoxyanilino) -6-methylpyrimidine, the dihydrochloride of which has M. P. 211-213 C.

From 4-chloro-2-a-naphthylamino-6-methylpyrimidine and fi-diethylaminoethylamine there is obtained 4 ,3 diethylaminoethylamino-2mnaphthylamino-G-methylpyrimidine, the dihydrochloride of which has M. P. 275-276 C. (decomp.).

From 4 chloro 2 4'-chloro-1'-naphthylamino) 6 methylpyrimidine and fl-diethylaminoethylamine there is obtained 4-B-diethylaminoethylamino 2 (4'-chloro-1-naphthylamino) -6-methylpyrimidine, the dihydrochloride of which has M. P. 294-295 C.

Example 11 15 parts of 4-chloro-2-(2'-methyl-4'-chloroanilino)-6-methylpyrimidine are heated with 13 parts of y-dibutylaminopropylamine at 120-130 C. for 8 hours. The reaction mixture is dissolved in dilute hydrochloric acid and basified with caustic soda solution. The liberated base is extracted with chloroform, the solution is dried and the chloro'orm distilled off in vacuo. The base then remaining is distilled in vacuo. It is 4 'y-dibutylaminopr0py1amino-2-(2'-methyl-4'- chloroanilino) 6 methylpyrimidine. It has a boiling point of 236 C./0.06 mm. and forms a picrate which, after crystallisation from a mixture of fl-ethoxyethanol and ethanol, melts at 157-159 C. To make the dihydrochloride the base is dissolved in 2-normal hydrochloric acid and the solution is evaporated to dryness in vacuo. The residue is crystallised from a mixture of ethyl alcohol and ethyl acetate whereby 4 7 dibutylaminopropylamino-2-(2-methy1- 4' chloroanilino)-6-methylpyrimidine dihydrochloride is obtained. M. P. 204-205 C.

In a similar way from 4chloro-2- (2'-methyl- 4-chloroanilino)-6-methylpyrimidine and 'y-diethylaminopropylamine there is obtained 4-'ydiethylaminopropylamino 2 (2-methyl-4'-chloroanilino)-6-methylpyrimidine, the dihydrochloride of which has M. P. 150-152 C.

Similarly from 4 chloro 2 (3'-chloro-4'- methylanilino) 6 methylpyrimidine and 7-Cliethylaminopropylamine there is obtained 4-7-dithylaminopropylamino 2-(3-chloro-4'-methylanilino)-6-methylpyrimidine, the dihydrochloride of which has M. P. 230-232 C.

From y-diethylaminopropylamine and 4-chloro 2 (3:4'-dimethylanilino) -6-methylpyrimidine there is obtained 4-v-diethylaminopropyl- -propylamino 2 (3'z5' dimethylanilino)-6- methylpyrimidine, the dihydrochloride of which has M. P. 306-308 C.

caustic soda solution.

From the same diamine and 4-chloro-2-(3':5'- dibromoanilino) -6-methylpyrimidine there is obtained 4 'y diethylaminopropylamino-2-(3:5- dibromoanilino)-6-methylpyrimidine, the dihydrochloride of which has M. P. 264-266 C.

From the same diamine and 4-chloro-2-(4'- bromoanilino) -6-methylpyrimidine there is obtained 4 'y diethylaminopropylamino-2-(4'- bromoanilino) -6-methylpyrimidine, the dihydrochloride of which has M. P. 255-25'7 C.

From 4 chloro-2-(4'-butylanilino) -6-methylpyrimidine and -diethylaminopropylamine there is obtained 4 -diethylaminopropylamino-Z-(4'- butylanilino) -6-methylpyrimidine, the dihydrochloride of which has M. P. 188-l90 C.

From 4 chloro-2-(4'-carbomethoxyanilino)- fi-methylpyrimidine and 'y-diethylaminopropylamine there is obtained 4-'y-diethylaminopropylamino 2 4-carbomethoxyani1ino)-6-methylpyrimidine, the dihydrochloride of which has M. P. 263-265 C.

From 4-chloro-2- (4-phenylanilino) -6-methylpyrimidine and -diethylaminopropylamine there is obtained 4-- -diethylaminopropylamino-Z-(4- phenylanilino) -6-methylpyrimidine, the dihydrochloride of which has M. P. 244-246 C.

From 4 chloro-2-(4-nitroanilino)-6-methylpyrimidine and -diethylaminopropylamine there is obtained 4- -diethylaminopropylamino-2-(4'- nitroanilino) -6-methylpyrimidine, the dihydrochloride of which has M. P. 226-232 C.

From the same diamine and 4-chloro-2-(4'- cyanoanilino) -6-methylpyrimidine there is obtained 4-Y-diethylaminopropylamino-2- (4'- cyanoanilino)-6-methylpyrimidine, the dihydrochloride of which has M, P. 249-251 C.

Example 12 6.3 parts of 2-p-chloroanilino-4-chloro-6- phenylpyrimidine are stirred and heated at 125-135 C. for 8 hours with 3 parts of fi-diethylaminoethylamine. The resulting melt is dissolved in 500 parts of hot dilute hydrochloric acid and basified with caustic soda solution. The base thus liberated is extracted with chloroform and the chloroform extract is evaporated. The oily residue is dissolved in parts of 5% aqueous acetic acid, filtered and the filtrate basified with The base which is again liberated is extracted with ether and the ether extract is dried over anhydrous potassium carbonate. After distilling oil the ether, the oily residue is dissolved in hot 2-normal hydrochloric acid. On cooling, 2-p-chloroanilino-4-B-diethylamino-ethylamino-G-phenylpyrimidine dihydrochloride separates out and is filtered off. After crystallisation from ethanol it has M. P. 277- 279 C. (decomp).

In a similar way from 2-p-methylanilino-4- chloropyrimidine and fi-diethylaminoethylamine there is obtained Z-p-methylanilino-4-;9-diethylaminoethylaminopyrimidine, the dihydrochloride of which has M. P. 220-221 C.

Similarly from 2-p-chloroanilino-4-chloropyrimidine and 7-diethylaminopropylamine there is obtained 2-p-chloroanilino-4- -diethylaminopropylaminopyrimidine, the dihydrochloride of which has M. P. 208-210 C.

From 2- p-chloroanilino-4-chloro-5 G-dimethylpyrimidine and Y-diethylaminopropylamine there is obtained 2-p-chloroanilino-4-' -diethylaminopropylamino-S:G-dimethylpyrimidine, the dihydrochloride of which has M. P. 277-279 C. (decomp.).

Example 13 1015 parts of Z-p-chloroanilino 4-chloro-5= ethyl- 6=methylpyrimidine" and 4;]; parts of fi-di methylaminoethylamine: are stirred and heated together at 1'25-135 C. for 8 hours. The resulting melt is dissolved in 500 parts of hot dilute hydrochloric acid and basified while still hotwith caustic sodasolution andthe base thus liberated is extracted with chloroform; The chloroform extractisshaken three times with 200' parts of aqueous acetic: acid and: the aceticacid: errtracts are combined and basiiied Withcaustic soda.- solution; The liberated base is extracted with chloroform, the chloroform solution is driedover anhydrous potassium carbonate and the chloroform is distilled ofi'. 2-'p-chloroani1ino-- 4 -;8- dimethylamin'oethylamino-5-ethyl-6=rnethylpyr-imidin'e remains as a solid. It may bepurifled by crystallisation from" petroleum ether (B. P. 60-80 0.) when it melts at1'1'5-11-6C.

To make the dihydrochloride the" crude base is dissolved in hot 2-normalhydrochloric acid. On cooling Z-p-chloroanilino 4 -cdimeth'yl aminoethylamino' 5 ethyl 6 -methylpyrimidine dihydrochloride crystallizes out; It may be'purifled. by recrystallisation from ethanol and then melts at 262 C. with decomposition.

By the reaction of the same chloro' compound with B- diethylaminoethylamine; 2 -p chloro= anilinoA-B- diethylaminoethylamino ii ethyl' 6- methylpyrimidine is obtained, M. P. 92 -94" C. after recrystallisation from petroleum ether (B; P: 4.0" 60 Ck). The dihydrochlo'ride, recrys tallised from a mixture ofethanol and acetone; has M. P. 258-260 C.

Similarly by using 'Y-dimethylaminopropylamine as the diamine, 2-p-chloroanilino-4 -7"- dimethylaminopropylamino-5-ethyl- 6- methylpyrimidine isobtained. Aftercrystallisatioii from petroleum ether (B; P. 100'-120 C.) it has M. P. 126-128 C. The dihydrochloride after cr stallisation from a mixture of ethanol and acetone has M. P. 244246 C.

Further, by interaction of 2=p-chloroanilino- 4-chloro-5-ethyl-G-methylpyrimidine and 'Y-diethylaminopropylamine there is obtained 2-pehloroanilino- 4-Y- diethylaminopropyIamino-E- ethyl-o methylpyrimidine which on crystallisaticn from petroleumether separates in colourless laminae; MI 1 1 68- C. The dihydrochloride crystallises from ethanol, an'd'then melts at2' 72*" 274" C. with decomposition.

Example I4- 10.9 parts of 2-pchloroani1in'o'-4-chloro-5- bromo-fi-methylpyrimidine and 5:3parts of Y-diethylaminopropylamine are stirred and heated together at'125"'-135 o. for 8'hours. The resulti'n'g melt is dissolved in hot dilute hydrochloric acid. The acid solution is basified with caustic soda solution and the base so liberated is extracted with ether, The ether extract is shaken twice with 100 parts of 5% aqueous acetic acid. The combined acetic acid extracts are basified with caustic soda-solution and'the liberated base again extracted with ether. After drying over anhydrous potassium carbonate, the ether isdistilled off. 2-p-chloroanilino=4 Y-diethy1amino propylamino-B-brorno 6 methylpyrimidine remains. This can be purified; if desired. by crys tallisation from petroleum ether (B. P. 60 -139 6.) and then has=M. P. 9496 C.

To form the dihydrochloride the crude base: is dissolved hr hotz-normal hydrochloric; acidi on: doolifig 2 -p"-chlordanilino-i-Y diethylamihorcpyiaminms-bromo' 6 methylpyrimidine dihyc'irochloride is obtained; After crystallisation fromethanol it has'L/I.PL 236233 C.

In a similar way from Z-p-chloroariiliho-- chio'ro 5-phenylpyrirnidine arid c-diethylaminoethyla'mine thereis obtained 2-p-chloroanilino- 4-3 diethylaminoethylamino-5-phenylpyrimidine which has M. P. 152 -153 C. Its dihy'drochloride has P. 264266 G. (decomp).

From 2--p-chioroanilino-4-chloro- 5 phenylifrhidine 7-diethylarninopropylamine ther is obtained Z-p-chIoroaniIinol -diethylaminopropylamino-fi-phenylpyrimidine of M. P. 155- 156 C.- The dihydrochioride' melts at 2G4-266 C... aftersoftening'at 282 C.

2 p -niethoxyanilino--chloro-5-phenylnyrimidine' and B-diethylaminoethylarnine there is obtained 2-p-niethoxyanilino-4-fi-diethylaminoethylamino-5-phenylpyrimidine of M. P. 158-'-l59-" C. The dihydrochloride has M. P. 209-211 C. (decomp).

From 2 -33-cliloi oaniliiiol chism-pyrimidine and the same cli nine" there is" obtained Z-pci or-oanilino i ,3-diethylaminoethylamino-pyrimidiine of MLP. 71 7 2 (3; Thedihydrochloride 1V5. P. 23 l-''238 C.

From 2=p-chlorcanilinol-chloro- 5 methylpyri'r ni aiine and the same diami'ne there is ob tained- 2-p chloroaniiinm l fi-diethylaminoethylamino-5 methy1pyrimidine of M. P. l06-l08 C. ihe dihydrochloride has M. P. 269 C; (decompfi 2-p-chlcroaniline 4-chloro5-: fi-dimethylpyrimidine and ,8 diethylarhinoethylamihe there a is obtained 2--p'-chloroanilino-4 c diethylamino ethylamino-5:ii-dimethylpyrirnidine of M. PL 160 -102 C The dihydrochlcride has M. P. 270- 271" C1 From Z p-cliloroanilino-4 chloro-5 6-dim'ethyl-' pyrimidine and s-diethylaminoethylamine there is obtained 2-p-chloroanilino-4-p-diethylaminm ethyl'ami'no-5=phenoxypyriinidineof M'. P. 84'-'85 C".-

Example-1 5 13.2 parts of 2-p-chloroanilino4 ethoxy-6 methylpyrimidine and 9.84 parts of 3 -diethylamino -i amiziopropane monohycrochio'ride are mixed and heated wi h stirring at 195 C. for 6 hours. After cooling the reaction mixture is dissolved in warm dilute hydrochloric acid and the resulting solution basiiied' with caustic soda. The base which is liberated is extracted with ether and the ether solutionis extracted with 5% acetic acid. The acetic acidextract is basified with caustic soda and the liberated base is extracted with chloroform. The chloroform solution is dried}. the chloroform is-distilled oiT and the residue is dissolved in-Z-normai hydrochloric acid. The solution is evaporated to dryness in vacuo at 5040 C. and the residue,.afterdrying, is crystallised twice from ethanol. There is thus obtained a-Y-diethylaminopropyiamino 2- p chiorcanilino-fi-methylpyri1nidinedihydrochloride, M. PI 250-252 0.

Example 16 8.6 parts of 2-p-chloroanilino i-chlbro-Ebenzyl-dmethylpyrimidine and 3.25 parts of ,B-diethylamincethylamine are stirred and heated togather l25-i35 C. for 8 hours. While still hot, the melt is dissolved in 400 parts of dilute hydrochloric aci'd and the hot solution is basified with: caustic soda solution. Theb'asewhich separates out is filtered-om washedwith water acid. The acid solution is clarified with charcoal and then again made alkaline with caustic soda solution. The base which is precipitated is extracted with chloroform. The chloroform solution is dried and the chloroform is distilled oif. The crude 2-p-chloroanilino-4-B-diethylaminoethylamino-5-benzyl-6 methylpyrimidine which remains is crystallised from petroleum ether (B. P. 60-30 C.) and then has M. P. 114- 115 C.

To make the dihydrochloride the crude base is dissolved in hot Z-normal hydrochloric acid; on cooling the dihydrochloride crystallizes out. It may be purified by recrystallisation from ethanol and then has M. P. 255-266 C. (decomp.).

In a similar way, from the same chloropyrimidine and 7-diethylaminopropylamine there is obtained 2-p-chloroanilino-4 Y diethylaminoethylamino-5-benzyl-G-methylpyrimidine of M. P. 104-105 C. The dihydrochloride has M. P. 274-276 C.

From the same chloropyrimidine and 'Y-dimethylaminopropylamine there is obtained 2-pchloroanilino4-Y-dimethylaminopropylamino-5- benzyl-G-methylpyrimidine of M. P. 112-114 C.

From 2-p-chloroanilino-4-chloro-5-benzyl-6- methylpyrimidine and 5-diethylamino-2-aminopentane there is obtained Z-p-chloroanilinol- 5-diethylamino-a-methylbutylamino-5-benzyl-6 methylpyrimidine, the dihydrochloride of which has M. P. 242-244 C.

Whereas the above description and examples illustrate many widely varied embodiments of the invention it will be apparent to one skilled in the art that many other embodiments and variations may be devised without departing from the spirit and scope thereof and accordingly it is to be understood that the invention is not in any way limited except as defined in the following claims.

In the claims below, the expression acidic substituents refers to radicals commonly recognized as ionizable, salt-forming, acid radicals, and typified by the carboxy, sulfonic acid and phenolic OH radicals. I

We claim:

1. As new compounds, the pyrimidine derivatives of the formula- Ami; t4

1' I-L ,NH-ANRR' wherein Am stands for an arylamino group which is free of acidic substituents, A is a linking radical selected from the group consisting of aliphatic, alicyclic and aliphatic-carbocyclic bivalent radicals, NRR is a strongly basic radical selected from the group consisting of primary, secondary and tertiary amine radicals and heterocyclic nitrogenous base radicals, X is a member of the group consisting of hydrogen and hydrocarbon radicals, Y is a member of the group consisting of hydrogen, halogen, lower alkyl, phenyl, benzyl and phenoxy,

2. As new compounds, the pyrimidine derivatives of the formula wherein Am stands for an arylamino group which is free of acidic substituents, A is an aliphatic link joining the N-atom of the NH group to the N-atom of the NRR'group and interposing therebetween at least two carbon atoms, NRR' is a clialkylamino group, X is a membe of the group consisting of hydrogen and hydrocarbon radicals, and Y is a member of the group consisting of hydrogen, halogen, lower alkyl, phenyl, benzyl and phenoXy.

3. As new compounds the -dialkylaminoalkylaminopyrimidines bearing in the 2-position an arylamino group free from acidic substituents and bearing in the 5-position a member selected from the group consisting of hydrogen, halogen, lower alkyl, phenyl, benzyl and phenoxy.

4. As new compounds, the 4-dialkylaminoalkylaminopyrimidines bearing in the 6-position a hydrocarbon radical, in the 2-position an arylamino group free from acidic substituents, and in' the 5- position a member selected from the group consisting of hydrogen, halogen, lower alkyl, phenyl, benzyl and phenoxy.

5. As new compounds, the -dialkylaminoalkylamino-5:G-dialkyl-pyrimidines bearing in the-2- position an arylamino group free from acidic substituents.

6. As new compounds the l-dialkylaminoalkylamino-5:G-dialkyl-pyrimidines bearing in the 2- position an anilino group free from acidic substituents.

7. As new compounds, the -dialkylaminoalkylamino-6-methyl-pyrimidines bearing in the 2- position an arylamino group free from acidic substituents.

8. As new compounds, the 4-dialkylaminoalkylamino-6-methyl-pyrimidines bearing in the 2-position an anilino group free from acidic substituents.

9. As new compounds, the Z-p-halogenoanilino- S-methyl-4-dialkylaminoalkylamino-pyrimidines.

10. As a new compound, 2-p-chloroanilino-4- ,e-diethylaminoethylamino-B-methyl-pyrimidine.

11. Process for the manufacture of new pyrimidine derivatives of the formula wherein Am stands for an arylamino group which is free of acidic substituents, A is a linking radical selected from the group consisting of allphatic, alicyclic and aliphatic-carbocyclic bivalent radicals, NRR' is a strongly basic radical selected from the group consisting of primary, secondary and tertiary amine radicals and heterocyclic nitrogenous base radicals, X is a member of the group consisting of hydrogen and hydrocarbon radicals, Y is a member of the group consisting of hydrogen, halogen, lower alkyl, phenyl, benzyl and phenoxy, which comprises the interaction of a diamine NH2ANRR' with a pyrimidine compound of the formulathe symbols A, Am, NRR, X and Y having the same meanings as before, and Z representing a, labile group which is reactive toward the hydrogen of a basic NH2 group.

12. A compound of the pyrimidine series characterized by carrying an aryl-amino radical in the 2-position, said aryl-amino radical being free of acidic substituents; and carrying the radical of a diamine in the 4-position, said diamine radical having the form NH-A-NRR wherein NRR' is a strongly basic radical selected from the 13. As a new compound, -v-dimethylaminogroup consisting of primary, secondary and terpropylamino-Z-p-chloroanilino-6-methy1-pyrimtiary amine radicals and heterocyclic nitrogenidine. Y

ous base radicals, while A is a saturated aliphatic FRANCIS HENRY SWINDEN CURD. hydrocarbon radical linking the two N-atoms of 5 CLIFFORD GORDON RAISON.

the diamine and interposing therebetween at least FRANCIS LESLIE ROSE,

two carbon atoms.

Certificate of Correction Patent No. 2,437,682. March 16, 1948. FRANCIS HENRY SWINDEN OURD ET AL.

It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows: Column 5, line 62, for chloroalinino read chloroamllino; column 10, line 61, after the word there insert is; line 75, for 246 C. read 264 0.; column 11, line 22, Example 10, for 2-4-chloro read 2-(4-chloro; column 14, line 33, for chloroaniline read chloroan'ilino; line 39, for 5:6-dimethyl read 5-phenowy; and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Ofiice.

Signed and sealed this 25th day of May, A. D. 1948.

THOMAS E MURPHY,

Assistant G'ommz'ssz'oner of Patents. 

